Resveratrol is a polyphenolic compound found in several plants. The compound includes double bonds and exists in two isoforms, trans-resveratrol and cis-resveratrol. The trans-isomer is the less stable form: trans to cis isomerization is facilitated by UV light and high pH, the cis to trans conversion is facilitated by low pH.
Resveratrol has extensive biological properties, including anticarcinogenic, anti-inflammatory, and estrogenic activities as well as cardiovascular protection, free-radical scavenging, inhibition/induction of apoptosis, and inhibition of platelet aggregation (See e.g., Mehdi S. et al., “Resveratrol addiction: To die or not to die.” Mol. Nutr. Food Res. 2009, 53, 115-128; Baur J. et al., “Therapeutic potential of resveratrol: the in vivo evidence.” Nature Reviews 5:493-506; and Ellen L. Robb and Jeffrey A. Stuart, “trans-Resveratrol as A Neuroprotectant.” Molecules 2010, 15, 1196-1212, and references therein in each). For example, resveratrol has been shown to exhibit in vitro as well as in vivo chemopreventive and chemotherapeutic activities (Delmas, D., et al., “Resveratrol as a chemopreventive agent: A promising molecule for fighting cancer” Curr. Drug Targets 2006, 7, 423-442). Indeed, resveratrol has been shown to exhibit chemopreventive and chemotherapeutic activities in all three stages of carcinogenesis (i.e., initiation, promotion, and progression) (de la Lastra, C. A., Villegas, I., Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications, Mol. Nutr. Food Res. 2005, 49, 405-430). Chronic inflammation can lead to cancer, diabetes, and cardiovascular, pulmonary, and neurological diseases. One of the possible mechanisms for the protective activities of resveratrol is downregulation of inflammatory responses. Resveratrol has been shown to inhibit inflammatory responses through the inhibition of synthesis of various proinflammatory mediators, modulation of prostaglandin synthesis, and through the inhibition of factors such as IL-1β, NF-κB, and AP-1 (Das, S., et al., “Resveratrol: A therapeutic promise for cardiovascular diseases” Recent Patents Cardiovasc. Drug Discov. 2007, 2, 133-138). Resveratrol protects the cardiovascular system in a multidimensional way. One effect includes inhibition of apoptotic cell death at very low concentrations, thereby providing protection from various diseases including myocardial ischemic reperfusion injury, atherosclerosis, and ventricular arrhythmias.
In rodents, resveratrol is absorbed mainly in the duodenum; studies in rat intestine indicate that approximately 20% of available resveratrol is absorbed. In such studies, the majority of the absorbed resveratrol was detected in plasma as conjugated derivatives, while only a minute amount was detected in an unconjugated form. (Andlauer, W., et al., Assessment of resveratrol bioavailability in the perfused small intestine of the rat, Drugs Exp. Clin. Res. 2000, 26, 47-55). In humans, resveratrol is glucuronated in the liver and sulfated in both the liver and the duodenum (Aggarwal, B. B., et al., Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies, Anticancer Res. 2004, 24, 2783-2840). The major derivatives of resveratrol glucuronidation are trans-resveratrol-3-O-glucuronide, trans-resveratrol-4′-O-glucuronide, and trans-resveratrol-3-O-sulfate (Yu, C., et al., Human, rat, and mouse metabolism of resveratrol, Pharm. Res. 2002, 19, 1907-1914). Kinetic analysis of resveratrol transformation suggests that, in the liver, glucuronidation is favored over sulfation, with similar rates of reaction.
In one study in humans, the bulk of an intravenous dose of resveratrol was converted to sulphate and gluconorated conjugates during absorption. (Walle, T., et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 32, 1377-1382 (2004)). An analysis of plasma metabolites after oral dosing detected both sulphate and glucuronide conjugates. Five distinct metabolites were present in the urine, including, resveratrol monosulphate, two isomeric forms of resveratrol monoglucuronide, dihydroresveratrol monosulphate and dihydroresveratrol monoglucuronide. It is well known that modifications such as glucuronidation and sulphation reduce the cell permeability of small molecules and aid in their excretion. This extensive modification by the small intestine and liver during absorption greatly reduce the bioavailability of resveratrol.